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首页> 外文期刊>Acta crystallographica. Section D, Biological crystallography. >Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition
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Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition

机译：的结构和功能特性芳基胺N-acetyltransferase病原体从其他分枝杆菌脓肿:差异分枝杆菌亚型和影响选择性抑制

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Mycobacterium abscessus is the most pathogenic rapid-growing mycobacterium and is one of the most resistant organisms to chemotherapeutic agents. However, structural and functional studies of M. abscessus proteins that could modify/inactivate antibiotics remain nonexistent. Here, the structural and functional characterization of an arylamine N-acetyltransferase (NAT) from M. abscessus [(MYCAB)NAT1] are reported. This novel prokaryotic NAT displays significant N-acetyltransferase activity towards aromatic substrates, including antibiotics such as isoniazid and p-aminosalicylate. The enzyme is endogenously expressed and functional in both the rough and smooth M. abscessus morphotypes. The crystal structure of (MYCAB) NAT1 at 1.8 angstrom resolution reveals that it is more closely related to Nocardia farcinica NAT than to mycobacterial isoforms. In particular, structural and physicochemical differences from other mycobacterial NATs were found in the active site. Peculiarities of (MYCAB) NAT1 were further supported by kinetic and docking studies showing that the enzyme was poorly inhibited by the piperidinol inhibitor of mycobacterial NATs. This study describes the first structure of an antibiotic-modifying enzyme from M. abscessus and provides bases to better understand the substrate/inhibitor-binding specificities among mycobacterial NATs and to identify/optimize specific inhibitors. These data should also contribute to the understanding of the mechanisms that are responsible for the pathogenicity and extensive chemotherapeutic resistance of M. abscessus.
机译：脓肿分枝杆菌是最致病性商务分枝杆菌,是其中一个最耐药生物化疗代理。m .脓肿蛋白质的研究修改/灭活抗生素仍然不存在。这里的结构和功能描述的芳基胺从m .脓肿N-acetyltransferase (NAT)((MYCAB) NAT1)报道。原核的NAT显示显著的N-acetyltransferase活动对芳香基板,包括抗生素等异烟肼和p-aminosalicylate。内生的表达和功能粗糙和光滑的m .脓肿形态类型。晶体结构(MYCAB) NAT1 1.8埃分辨率显示,它是更密切诺卡氏菌属相关farcinica NAT比分枝杆菌亚型。和其他理化区别分枝杆菌NATs活性位点被发现。(MYCAB) NAT1进一步的特点支持动态和对接研究显示酶抑制不当了分枝杆菌NATs piperidinol抑制剂。研究描述的第一个结构从m .脓肿和antibiotic-modifying酶为更好地理解提供基础衬底/ inhibitor-binding特异性分枝杆菌NATs和识别/优化特定的抑制剂。有助于理解机制负责致病性和广泛的化疗抵抗的M。脓肿。

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